1. health and fitness
2. disease

ORIGINAL INVESTIGATION
A New Pharmacological Treatment
for Intermittent Claudication:
Results of a Randomized, Multicenter Trial
Hugh G. Beebe, MD; David L. Dawson, MD; Bruce S. Cutler, MD; J. Alan Herd, MD;
D. Eugene Strandness, Jr, MD; Enoch B. Bortey, PhD; William P. Forbes, PharmD
Background: Effective medication is limited for the
relief of intermittent claudication, a common manifestation of arterial occlusive disease. Cilostazol is a potent
inhibitor of platelet aggregation with vasodilation
effects.
Objective: To evaluate the safety and efficacy of cilostazol for the treatment of intermittent claudication.
Methods: Thirty-seven outpatient vascular medicine clin-
ics at regional tertiary and university hospitals in the
United States participated in this multicenter, randomized, double-blind, placebo-controlled, parallel trial. Of
the 663 screened volunteer patients with leg discomfort, a total of 516 men and women 40 years or older with
a diagnosis of moderately severe chronic, stable, symptomatic intermittent claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo
twice a day orally for 24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing, patient-based quality-of-life measures, global
assessments by patient and physician, and cardiovascular morbidity and all-cause mortality survival analysis.
improvement in maximal walking distance (P,.001 vs
placebo); those who received cilostazol, 50 mg, twice a
day had a 38% geometric mean improvement in maximal walking distance (P,.001 vs placebo). These percentages translate into an arithmetic mean increase in
distance walked, from 129.7 m at baseline to 258.8 m at
week 24 for the cilostazol, 100 mg, group, and from
131.5 to 198.8 m for the cilostazol, 50 mg, group. Geometric mean change for pain-free walking distance
increased by 59% (P,.001) and 48% (P,.001), respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg,
groups. These results were corroborated by the results of
subjective quality-of-life assessments, functional status,
and global evaluations. Headache, abnormal stool
samples or diarrhea, dizziness, and palpitations were the
most commonly reported potentially drug-related
adverse events and were self-limited. A total of 75
patients (14.5%) withdrew because of any adverse event,
which was equally distributed between all 3 treatment
groups. Similarly, there were no differences between
groups in the incidence of combined cardiovascular
morbidity or all-cause mortality.
Conclusion: Compared with placebo, long-term use of
Results: The clinical and statistical superiority of active
treatment over placebo was evident as early as week 4,
with continued improvement at all subsequent time
points. After 24 weeks, patients who received cilostazol,
100 mg, twice a day had a 51% geometric mean
From the Jobst Vascular Center,
Toledo, Ohio (Dr Beebe);
Wilford Hall Medical Center
(Dr Dawson), Lackland Air
Force Base, San Antonio, Tex;
University of Massachusetts
Medical Center (Dr Cutler),
Worcester; The Methodist
Hospital, Houston, Tex
(Dr Herd); University of
Washington Medical School,
Seattle (Dr Strandness); and
Otsuka America
Pharmaceutical Inc, Rockville,
Md (Drs Bortey and Forbes).
A complete list of study
investigators appears on
page 2049.
I
cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent
claudication.
Arch Intern Med. 1999;159:2041-2050
NTERMITTENT claudication is a de-
bilitating condition that severely restricts a person’s ability
to walk and thus, to perform ordinary daily activities of independent living. Intermittent claudication, a
pain or ache in muscle groups of the lower
limbs that occurs with walking and subsides with rest, is caused by a deficient
blood supply in exercising muscle and is
associated with lower extremity arterial
occlusive disease.1 In the United States,
lower extremity arterial occlusive disease
may affect up to 20% of the older adult
population.2 Approximately 70% of patients with lower extremity arterial occlusive disease present with claudication as
their sole symptom.3 A patient with intermittent claudication may experience a progressive decline in physical functioning—as the claudication worsens, the less
the patient walks; the less the patient exercises, the more general cardiovascular
status deteriorates.
In the United States, the most common pharmacological approach to
intermittent claudication is pentoxifylline. Additional classes of drugs include
vasodilators, antiplatelet agents, anticoagulants, prostaglandins, and prostaglandin analogs that have been suggested or
tested as possible treatment for claudication and vary in result. Clinical trials demonstrating the effectiveness of all these
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©1999 American Medical Association. All rights reserved.
PATIENTS AND METHODS
STUDY DESIGN
This multicenter, randomized, double-blind, 24-week,
placebo-controlled, parallel trial assessed the safety and
efficacy of cilostazol, 100 mg or 50 mg, taken orally
twice a day in relieving intermittent claudication. A total
of 37 outpatient vascular clinics in tertiary hospitals and
medical schools throughout the United States participated. Men and women 40 years or older who had at
least a 6-month history of stable, symptomatic intermittent claudication secondary to lower extremity arterial
occlusive disease, who demonstrated reproducible walking distances on screening treadmill tests, and who terminated all screening treadmill tests solely because of
claudication pain, were eligible for inclusion in the
study. During a minimum 3-week screening period,
patients had to demonstrate evidence of stable disease by
having pain-free walking distance (initial claudication
distance) results between 30 and 200 m on 2 consecutive treadmill tests, with 25% or more variance between
results. The treadmill test was a constant-rate, constantgrade design with a 12.5% incline and speed of 3.2 km/h
(2 mph). Additional entry criteria were a resting ankle
brachial index of 0.90 or less and a 10 mm Hg or more
decrease in ankle artery blood pressure following the
onset of maximal walking distance (absolute claudication distance).
Exclusionary criteria included ischemic pain at rest,
gross obesity, childbearing potential, hypertension
(.200 mm Hg systolic or .100 mm Hg diastolic supine
resting blood pressure), current metastatic malignant
neoplasm, exercise-limiting cardiac disease, and history
of bleeding tendencies, as well as concomitant use of
antiplatelet, anticoagulant, vasoactive, hemorrheologic,
or nonsteroidal anti-inflammatory agents. Occasional
use of acetaminophen, diclofenac sodium, or nitroglycerin was allowed. Before undergoing screening procedures, patients signed an informed consent form
approved by the institutional review board at each participating center.
agents are limited. Medical therapy has routinely included exercise programs and the modification of risk
factors such as smoking, sedentary lifestyle, and diet, but
patient participation and compliance are often disappointing. Arterial bypass or percutaneous transluminal
angioplasty may be appropriate and effective for some
patients with severe, incapacitating claudication.4 However, these procedures are not indicated for the many patients whose severity of intermittent claudication does
not warrant the attendant risks of invasive procedures.
An effective medication that clearly improves physical
functioning could provide an important addition to the
limited therapeutic armamentarium currently available.
Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)
butoxyl]-3,4-dihydro-2(1H)-quinolinone, OPC-13013,
CAS 73963-72-1) is a type III phosphodiesterase inhibitor. Although its mechanism of action is not fully un-
The sample size required to ensure 80% power of
detecting a doubling of the cardiovascular morbidity and
all-cause mortality event rate was 143 patients per group,
based on a 5% significance level (2-sided). Therefore,
enrollment was set at 150 patients per treatment group to
show a between-group difference in the combined end
point of morbidity and mortality. Because fewer patients
were needed for the primary efficacy end point of
improvement in treadmill walking distances, the protocol
allowed 8 investigational centers to waive the requirement
for patients randomized at their centers to undergo
treadmill testing and Doppler-measured limb pressure
assessments. These randomized patients, primarily
monitored for safety and exempt from efficacy treadmill
testing and Doppler data, underwent all other assessments and were evaluated for safety the same as the nonexempt patients (ie, those monitored for safety plus efficacy treadmill testing).
ASSIGNMENT AND BLINDING
On completing the screening period, eligible patients
were randomized to double-blind treatment with 50 mg
or 100 mg of cilostazol or placebo. Randomization of eligible patients was stratified by each clinical center. A
master randomization list of patient code assignments to
the test medications (100 mg, 50 mg, or placebo) was
developed using a permuted-block design. The master
list was then forwarded to the drug packaging company,
where a separate medication supply was prepared for
each unique patient code. All 3 test medications had a
similar appearance. Patient compliance with study medication was assessed by having the patient return all used
and unused treatment cards at each scheduled dispensing visit.
PATIENT EVALUATION
Patients were evaluated 3 times at baseline and at weeks 4, 8,
16, 20, and 24. Efficacy evaluations included exercise treadmill testing assessments of pain-free and maximal walking distances; Doppler-measured bilateral peripheral limb pressures assessed before exercise and 1, 5, and 9 minutes following
derstood, cilostazol is thought to inhibit cyclic adenosine monophosphate phosphodiesterase, which leads to
an increase in cyclic adenosine monophosphate in platelets and blood vessels, and to promote the effect of prostaglandin I2, an endothelial cell-derived substance that
inhibits platelet aggregation and relaxes vascular smooth
muscle. Cilostazol is an antithrombotic agent that inhibits platelet aggregation and increases vasodilation. Its
antiplatelet activity is 10 to 30 times more potent than
aspirin.5
This study evaluated the safety and efficacy of cilostazol in relieving intermittent claudication. We sought
to find whether cilostazol, 100 mg and 50 mg, taken orally
twice a day, will significantly improve the pain-free and
maximal walking distances among individuals with intermittent claudication when compared with baseline and
placebo.
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©1999 American Medical Association. All rights reserved.
exercise; quality-of-life and functional status questionnaires, and patient and physician end-of-treatment global
therapeutic assessments. A survival analysis of combined
all-cause mortality and cardiovascular morbidity was done.
For all-cause mortality and cardiovascular morbidity assessment, an independent study committee, blinded to treatment assignment, adjudicated all patient deaths and serious adverse events according to protocol-defined criteria
(Table 1). Additional safety assessments included adverse events, vital signs, physical examination findings, clinical laboratory results, electrocardiograms, and 48-hour
Holter monitoring.
The functional status questionnaires, administered
by centralized telephone interview, included the Medical
Outcomes Scale Short Form-36(SF-36)—a generalized
measure of quality of life, and 2 disease-specific questionnaires: the Walking Impairment Questionnaire (WIQ)
and Claudication Outcome Measures (COM). The SF-36
includes 8 subscales that measure patients’ perception of
their health status in 3 main areas: (1) physical health
concepts (bodily pain, physical function, and role–
physical); (2) mental health concepts (social functioning,
role–emotional, and mental health); and (3) combined
physical-mental health concepts (general health perception and vitality).6 The WIQ characterizes walking speed,
walking distance, and symptoms associated with walking
difficulty to assess the degree of walking impairment and
efficacy of therapeutic intervention in improving walking
ability.7 The COM assesses the severity of walking pain
and discomfort while walking short and long distances,
the degree to which claudication pain imposes physical
limitations, and the extent to which the pain affects daily
and social activities or causes worry and concern. The
COM questionnaire was developed by the study sponsor
and has not been independently validated. Scores were
arranged so that a higher score was always indicative of
better functioning.
STATISTICAL ANALYSIS
All statistical analyses were based on the intent-to-treat population (ie, patients having a baseline and at least one postbaseline assessment). For safety analyses, this included all
RESULTS
PATIENT DISPOSITION
As shown in the flow diagram of patient disposition
(Figure 1), 663 patients were screened for eligibility,
516 of whom were randomly assigned to treatment:
175 patients received cilostazol, 100 mg, twice a day,
171 patients received cilostazol, 50 mg, twice a day,
and 170 patients received placebo. All 516 patients
were assessed for safety. A subgroup of 419 patients
(safety and efficacy subgroup), which represented
81.2% (419/516) of the randomized population, were
included in the efficacy intent-to-treat analysis of
treadmill data. The additional 97 patients (safety-only
subgroup), who were randomized but did not undergo
postrandomization treadmill tests, were equally dis-
516 randomized patients. Demographic, medical history, and
baseline data were summarized by treatment group and analyzed for comparability across groups using the KruskalWallis test for continuous variables and the Cochran-MantelHaenszel test for categorical variables.
The primary efficacy variables were pain-free and
maximal walking distances at week 24. To reduce the
variability that is typically seen with walking distance data
and the impact of extreme values, pain-free and maximal
walking distances were analyzed primarily in terms of the
logarithm of the ratio of distance walked over distance
walked at baseline. Log transformation allowed analysis of
all patient data, since there was no justification for discarding extreme observations. If the Kruskal-Wallis test
for these variables was significant, a Wilcoxon rank sum
test8 for pairwise comparisons was performed. The P values for the pairwise tests, cilostazol, 100 mg, vs placebo
and cilostazol, 50 mg, vs placebo, were considered the
primary inferential evidence, and a P value of .05 or less
was considered statistically significant. The per-protocol
primary analysis for analyzing treadmill data was last
observation carried forward, in which the postrandomization values were carried forward to populate the missing
visit data. In addition to the analysis using log transformation, walking distance in meters was provided for a longitudinal clinical perspective.
Secondary efficacy variables included functional status questionnaires, global therapeutic assessment, and survival analysis of combined cardiovascular morbidity and
all-cause mortality. For the quality-of-life and patient questionnaires, repeated-measures analysis of variance was used
and treatment comparisons were performed using the
Kruskal-Wallis and Wilcoxon rank sum tests on change from
baseline values. Between-group differences in the global
therapeutic assessment were evaluated by the CochranMantel-Haenszel9 test and in the combined cardiovascular morbidity and all-cause mortality end point by the
Kaplan-Meier product limit estimator.
In the analysis of safety data, changes in safety variables from baseline were summarized using descriptive
statistics and shift tables as appropriate. A 2-sided Fisher
exact test8 was used to assess adverse events between
groups.
tributed between treatments. Of the 419 patients in
the efficacy intent-to-treat group, 316 (75.4%) completed all treadmill visits up to week 24. The 98
patients (18.9%) who withdrew from study participation, 75 (14.5%) of whom because of any adverse
events, were also equally distributed between treatment groups.
Demographic data are shown in Table 2. Randomized patients were primarily white (88.6%) and
male (76.0%), with an average age of 64.6 years
(range, 41-88 years). A total of 93.4% (482/516) of
patients had a positive history for cigarette smoking,
and more than one third were current smokers.
Patients with diabetes accounted for 28.1% (145/516)
of the population. There were no clinically or statistically relevant differences between the treatment
groups at baseline.
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Screened Patients
(N=663)
Table 1. Protocol-Defined Criteria
for Cardiovascular Morbidity
1. Myocardial infarction verified by clinical symptoms, enzyme
changes, and electrocardiogram changes indicative of myocardial
infarction
2. Cerebrovascular infarct (stroke) verified by neurologic deficit lasting
longer than 24 hours confirmed by angiography, computed
tomographic scan, or magnetic resonance imaging
3. Arterial revascularization, including angioplasty or surgical vascular
reconstruction:
a. Procedures for peripheral vascular disease, including lower
extremity bypass*
b. Other procedures, including coronary artery bypass graft, carotid
endarterectomy, and renal procedures*
4. Amputation for ischemia
*Both 3a and 3b classifications were defined by the executive committee
post hoc to clarify outcomes.
TREADMILL DATA
Table 3 shows the results of the primary efficacy analysis of treadmill data and geometric mean change from
baseline using last observation carried forward at week
24, as well as secondary results at the interim time points
of weeks 4, 8, 16, and 20. For ease of interpretation, geometric mean change can be converted to geometric mean
percent change by the following simple calculation: Geometric Mean Percent Change = [(Geometric Mean) − 1]
3 100.
At week 24, pain-free and maximal walking distances were statistically significantly greater in both cilostazol groups compared with the placebo group. At week
24, the improvement in pain-free walking distance was
59% in the cilostazol, 100 mg, group and 48% in the cilostazol, 50 mg, group compared with 20% in the placebo
group (P,.001 for cilostazol, 100 mg, twice a day vs placebo and P,.001 for cilostazol, 50 mg, twice a day vs
placebo). Results were similar for maximal walking distance at week 24, with patients in both cilostazol groups
showing improvement: 51% in the cilostazol, 100 mg, group
and 38% in the cilostazol, 50 mg, group, compared with
15% in the placebo group (P#.001 for cilostazol, 100 mg,
twice a day vs placebo; P,.001 for cilostazol, 50 mg, twice
a day vs placebo).
The superiority of active treatment over placebo was
observed as early as week 4 and was maintained at all subsequent time points up to week 24. As shown in Figure 2
and Figure 3, the magnitude of improvement in both
pain-free and maximal walking distances increased over
time. Also shown in Table 3 is the mean walking distance in meters walked, which reinforces the significance of the geometric mean change data. Patients taking cilostazol, 100 mg, twice a day nearly doubled their
walking distances on the treadmill after 24 weeks of treatment, from a pain-free walking distance of 70.4 m at baseline to 137.9 m at week 24, and a maximal walking distance of 129.7 m at baseline to 258.8 m at week 24.
Patients taking cilostazol, 50 mg, twice a day increased
their walking distances greater than 1.5-fold after 24 weeks
of treatment, from a pain-free walking distance of 66.5
m at baseline to 115.1 m at week 24, and a maximal walk-
Not Randomized
(Did Not Meet Eligibility Requirements)
(n=147)
Randomized
(N=516)
Cilostazol, 100 mg,
Twice Daily (n=175)
Cilostazol, 50 mg,
Twice Daily (n=171)
Placebo
(n=170)
Efficacy Intent-to-Treat
Population
(n=140)
Efficacy Intent-to-Treat
Population
(n=139)
Efficacy Intent-to-Treat
Population
(n=140)
Patients Studied
for Safety Only∗
(n=35)
Patients Studied
for Safety Only
(n=32)
Patients Studied
for Safety Only
(n=30)
Withdrawn
Adverse Events† (n=26)
Other‡ (n=11)
Withdrawn
Adverse Events (n=25)
Other (n=7)
Withdrawn
Adverse Events (n=24)
Other (n=5)
Completed Trial
(n=138)
Completed trial
(n=139)
Completed Trial
(n=141)
Completed Every Test§
(n=106)
Completed Every Test
(n=108)
Completed Every Test
(n=102)
Figure 1. Disposition of patients in the trial. Asterisk indicates patients did
not undergo postrandomization treadmill testing; dagger, adverse event,
death, or marked deterioriation; double dagger, failed screening, inability to
continue, noncompliance, or lack of response to study drug; and section
mark, patients from efficacy intent-to-treat population who completed all
treadmill visits.
ing distance of 131.5 m at baseline to 198.8 m at week
24. Treatment-by-center interactions were investigated
and showed no significance.
FUNCTIONAL STATUS QUESTIONNAIRES
Improvements in walking distances were paralleled by
patients’ perceived physical improvements, as assessed
by the SF-36, WIQ, and COM. Table 4 summarizes results of the functional status questionnaires at week 24.
For the physical health concepts domain of the SF-36,
both cilostazol groups were significantly superior to placebo at week 24 in the physical function and bodily pain
scales. The role–physical domain improved in the cilostazol groups, although it did not reach statistical significance. There was no significant difference between
either cilostazol group and placebo for the mental health
concepts domain. For the WIQ at week 24, both cilostazol groups were superior to placebo for walking speed
and walking distance. Statistically significant improvements were seen in the following COM scales: walking
pain/discomfort, change in walking pain/discomfort, and
walking pain/discomfort related to ability to perform
physical activities. For all other domains and subscales,
the cilostazol groups were not significantly different from
the placebo group.
GLOBAL THERAPEUTIC ASSESSMENT
Generally, more patients and investigators judged claudication symptoms at the end of treatment to have been
improved by cilostazol than by placebo (Table 5). Significantly more patients in both cilostazol groups rated
their outcomes as “better” or “much better” compared
with pretreatment: 53.2% in the cilostazol, 100 mg, group,
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Table 2. Demographics of All Randomized Patients
Parameter
Age, y
Mean ± SE
Range
Age category, No. (%)
,65 y
$65 y
Sex, No. (%)
Male
Female
Race, No. (%)
White
Black
Hispanic
Asian
Other
Weight, kg
No.
Mean ± SE
Range
Height, cm
No.
Mean ± SE
Range
Diabetes, No. (%)
Yes
No
Cigarettes, No. (%)
Never
Previous
Current
Pack-years†
No.
Mean ± SE
Range
Other tobacco products, No. (%)
Never
Previous
Current
Alcohol, No. (%)
Never
Previous
Current
Cilostazol, 100 mg,
Twice Daily
(n = 175)
Cilostazol, 50 mg,
Twice Daily
(n = 171)
64.3 ± 8.5
42-85
64.5 ± 9.9
41-88
65.1 ± 9.3
41-86
.67
82 (46.9)
93 (53.1)
77 (45.0)
94 (55.0)
75 (44.1)
95 (55.9)
.87
130 (74.3)
45 (25.7)
131 (76.6)
40 (23.4)
131 (77.1)
39 (22.9)
.81
154 (88.0)
15 (8.6)
3 (1.7)
2 (1.1)
1 (0.6)
152 (88.9)
17 (9.9)
2 (1.2)
0 (0)
0 (0)
151 (88.8)
15 (8.8)
4 (2.4)
0 (0)
0 (0)
.57
175
78.6 ± 16.1
41.8-115.0
171
79.6 ± 15.5
42.0-132.7
170
78.8 ± 16.0
47.7-129.4
.83
Placebo
(n = 170)
P*
175
171.6 ± 9.5
142.0-193.0
171
172.2 ± 9.4
146.0-196.0
170
171.9 ± 8.9
152.0-196.0
.88
46 (26.3)
129 (73.7)
51 (29.8)
120 (70.2)
48 (28.2)
122 (71.8)
.76
12 (6.9)
102 (58.3)
61 (34.9)
11 (6.4)
98 (57.3)
62 (36.3)
11 (6.5)
84 (49.4)
75 (44.1)
.45
163
51.4 ± 25.0
5.0-160.0
160
47.3 ± 28.2
1.0-175.0
158
47.5 ± 26.5
0.6-120.0
.14
152 (86.9)
17 (9.7)
6 (3.4)
153 (89.5)
17 (9.9)
1 (0.6)
154 (90.6)
13 (7.6)
3 (1.8)
.36
24 (13.7)
45 (25.7)
106 (60.6)
28 (16.4)
45 (26.3)
98 (57.3)
23 (13.5)
50 (29.4)
97 (57.1)
.86
*Fisher exact test for categoric variables and Wilcoxon rank sum test for continuous variables.
†Pack-years indicates packs of cigarettes per day times number of years smoked.
54.1% in the cilostazol, 50 mg, group, and 37.3% in the
placebo group (P = .002 for cilostazol, 100 mg, twice a
day vs placebo; P = .01 for cilostazol, 50 mg, twice a day
vs placebo). Significantly more investigators evaluating
patients in the cilostazol, 100 mg, group vs placebo also
rated improvement as “better” or “much better” (48.5%
vs 33.1%; P = .003).
by the executive committee (Table 6). Figure 4 depicts the results of the life-table analysis and illustrates
no statistically significant differences between treatment groups in the probability of survival without cardiovascular morbidity or all-cause mortality during 24
weeks of therapy (P = .71).
SAFETY
CARDIOVASCULAR MORBIDITY AND
ALL-CAUSE MORTALITY
A life-table analysis was performed to determine any between-group differences in the incidence of combined cardiovascular morbidity and all-cause mortality. A total of
34 patients met the criterion of cardiovascular morbidity (n = 29) or all-cause mortality (n = 5) as determined
The most common ($10% incidence) adverse events
judged by investigators to be potentially drug related were
headache, abnormal stool samples (ie, loose and soft stool
samples), diarrhea, dizziness, and palpitation (Table 7).
Patients who received cilostazol reported a significantly
greater incidence of headache, abnormal stool samples,
diarrhea, and palpitation than patients who received pla-
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Table 3. Treadmill Test Results in the Efficacy Intent-to-Treat Population: Geometric Mean Change
From Baseline and Mean Distance in Meters Using Last Observation Carried Forward
Geometric Mean Change From Baseline
Mean Walking Distance
in Meters (No.)
Pairwise Comparison
P Value
Week
Cilostazol,
100 mg,
Twice Daily
Cilostazol,
50 mg,
Twice Daily
Placebo
Cilostazol,
100 mg,
Twice Daily
vs Placebo
Cilostazol,
50 mg,
Twice Daily
vs Placebo
Baseline
4
8
16
20
24
...
1.12
1.31
1.43
1.49
1.59
...
1.15
1.26
1.42
1.44
1.48
...
1.05
1.14
1.15
1.20
1.20
Pain-Free Walking Distance
...
...
.003
.003
.002
.009
,.001
,.001
.002
.002
,.001
,.001
Baseline
4
8
16
20
24
...
1.14
1.34
1.41
1.49
1.51
...
1.12
1.26
1.35
1.35
1.38
...
1.02
1.09
1.11
1.14
1.15
Maximal Walking Distance
...
...
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
60
40
30
20
10
Cilostazol,
50 mg,
Twice Daily
Placebo
70.4 (140)
85.7 (131)
100.3 (134)
112.4 (134)
127.1 (134)
137.9 (140)
66.5 (139)
80.1 (135)
90.0 (136)
103.0 (136)
111.1 (136)
115.1 (139)
72.4 (140)
75.4 (132)
90.0 (135)
91.9 (135)
95.1 (135)
95.5 (140)
129.7 (140)
153.4 (131)
186.2 (134)
216.0 (134)
243.0 (134)
258.8 (140)
131.5 (139)
148.0 (135)
170.2 (136)
183.7 (136)
186.8 (136)
198.8 (139)
147.8 (140)
142.1 (132)
157.5 (135)
161.9 (135)
164.7 (135)
174.6 (140)
Cilostazol, 100 mg, Twice Daily
Cilostazol, 50 mg, Twice Daily
Placebo
50
Change From Baseline, %
50
Change From Baseline, %
60
Cilostazol, 100 mg, Twice Daily
Cilostazol, 50 mg, Twice Daily
Placebo
Cilostazol,
100 mg,
Twice Daily
40
30
20
10
0
0
4
8
12
16
20
24
4
Week
8
12
16
20
24
Week
Figure 2. Geometric mean percent change in pain-free walking distance over
time in the efficacy intent-to-treat population using last observation carried
forward.
Figure 3. Geometric mean percent change in maximal walking distance over
time in the efficacy intent-to-treat population using last observation carried
forward.
cebo (P,.05). Most headaches were mild or moderate
and occurred during the first 2 weeks of therapy. Six patients discontinued use of study medication because of
persistent or severe headache: 4 in the cilostazol, 100 mg,
group and 2 in the cilostazol, 50 mg, group. Of the 28
patients who experienced palpitations, most reported them
to be mild. Twenty-four (86%) of the 28 patients who
reported palpitations had a history of hypertension, cardiac disease, or both. Seven patients withdrew from the
study because of palpitation: 4 in the cilostazol, 100 mg,
group and 3 in the cilostazol, 50 mg, group. Most cases
of abnormal stool samples and diarrhea were mild to moderate. One patient with a history of gastrointestinal problems had continuous, severe diarrhea and withdrew from
the study.
Significant positive changes were observed in highdensity lipoprotein cholesterol and triglyceride levels in
patients receiving cilostazol compared with those receiv-
ing placebo. The least-squares mean of high-density lipoprotein increased 0.16 (6.3 mg/dL), 0.09 (3.5 mg/dL),
and 0.04 mmol/L (1.7 mg/dL) after 24 weeks of treatment
for the 100-mg, 50-mg, and placebo groups, respectively (P,.001 for 100 mg vs placebo; P = .18 for 50 mg
vs placebo). All 3 treatment groups showed a trend toward reduced triglyceride and low-density lipoprotein
cholesterol levels during the study, but greater and more
immediate reductions in triglyceride level were observed in
the 2 cilostazol groups. Compared with placebo, the leastsquares mean change from baseline for triglyceride level
was −1.09, −0.82, and −0.50 mmol/L (–96.9, –72.3, and
– 44.0 mg/dL) for the 100-mg, 50-mg, and placebo treatment groups, respectively (P,.001 for 100 mg vs placebo; P = .046 for 50 mg vs placebo). There was a trend
toward reduction in total cholesterol level in patients receiving cilostazol. No other clinically relevant laboratory changes were seen.
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Table 4. Results of the Functional Status Questionnaires at Week 24 for All Patients With at Least One Data Point*
Mean Score (Mean Change From Baseline)
Cilostazol, 100 mg,
Twice Daily
(n = 137)
Scale (Range)
Cilostazol, 50 mg,
Twice Daily
(n = 135)
Placebo
(n = 141)
3-Way
Comparison
P Values†
Medical Outcomes Scale Short Form-36 Questionnaire
Physical health (0-100)
Physical function
Role–physical
Bodily pain
Mental health (0-100)
Social function
Role–emotional
Mental health
Walking speed (0-1)
Walking distance (0-1)
Change in pain/discomfort (0-4)
Pain/discomfort daily activities (0-4)
Pain/discomfort physical activities (0-4)
Pain/discomfort social activities (0-4)
Walking pain/discomfort (0-4)
Worry/concern due to pain (0-4)
61.6 (7.1)
61.3 (5.3)
62.9 (7.2)
59.3 (8.0)
57.6 (4.4)
58.4 (4.6)
53.8 (2.0)
49.8 (−2.8)
54.0 (−1.8)
.02
.13
.002
86.3 (1.0)
91.7 (2.9)
82.2 (2.5)
85.2 (0.9)
90.1 (0.0)
80.3 (−1.5)
82.5 (0.4)
84.2 (−1.66)
79.6 (0.9)
.93
.29
.03
Walking Impairment Questionnaire
0.56 (0.1)‡
0.50 (0.2)
0.53 (0.2)
0.47 (0.2)
0.44 (0.1)
0.38 (0.1)
.002
.01
Claudication Outcome Measures
. . . (2.8)
. . . (2.7)
2.8 (0.4)
2.8 (0.5)
2.5 (0.5)
2.3 (0.5)
3.5 (0.3)
3.4 (0.4)
2.4 (0.7)
2.1 (0.7)
3.0 (0.8)
2.8 (0.6)
. . . (2.4)
2.5 (0.2)
2.1 (0.2)
3.2 (0.3)
1.8 (0.4)
2.6 (0.5)
,.001
.07
,.001
.85
.005
.05
*For all scales, a higher score is indicative of better functioning. Ellipses indicate data not applicable.
†Three-way comparison based on the Kruskal-Wallis test on change from baseline. Pairwise comparisons based on the Wilcoxon rank sum test on change from
baseline.
‡n = 136.
Table 5. Global Therapeutic Assessment by Patient and Investigator at Week 24
Judgment
By investigator
Much better
Better
Unchanged
Worse
Much worse
Unknown
By patient
Much better
Better
Unchanged
Worse
Much worse
Unknown
Cilostazol, 100 mg,
Twice Daily
(n = 171), No. (%)
Cilostazol, 50 mg,
Twice Daily
(n = 170), No. (%)
25 (14)
58 (33)
80 (46)
2 (1)
0 (0)
6 (3)
20 (12)
55 (32)
86 (50)
3 (2)
1 (1)
5 (3)
12 (7)
44 (26)
99 (58)
10 (6)
2 (1)
2 (1)
.03
31 (18)
60 (34)
69 (39)
3 (2)
0 (0)
8 (5)
28 (16)
64 (37)
70 (41)
5 (3)
2 (1)
1 (1)
23 (14)
40 (24)
84 (49)
15 (9)
3 (2)
4 (2)
.002
Placebo
(n = 169), No. (%)
3-Way
Comparison
P Value*
*Based on Cochran-Mantel-Haenszel test.
A dose-dependent increase in heart rate was observed for patients receiving cilostazol. Mean change from
baseline in apical pulse at week 24 was 7.2/min, 3.7/
min, and 0.2/min for the cilostazol, 100 mg, cilostazol,
50 mg, and placebo groups, respectively. Blood pressure remained stable during the study, with a slight trend
toward a dose-dependent decrease in blood pressure in
both cilostazol groups compared with the placebo group.
No relevant findings were observed in the other assessed safety parameters.
COMMENT
Patients with intermittent claudication as their only manifestation of lower extremity arterial occlusive disease do
not have limb-threatening ischemia, and have several options for symptomatic relief. Percutaneous transluminal
angioplasty and arterial bypass are costly, may be associated with significant morbidity or mortality, and should
therefore be generally reserved for treatment of severe,
incapacitating claudication. 4 Patients with mild-to-
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Table 6. Incidence of Deaths or Cardiovascular Events as Adjudicated by the Executive Committee
All Randomized Patients
Event
Cilostazol, 100 mg,
Twice Daily
(n = 175), No. (%)
Cilostazol, 50 mg,
Twice Daily
(n = 171), No. (%)
Placebo
(n = 170), No. (%)
Total
(n = 516), No. (%)
2 (1.1)
3 (1.7)
0 (0)
4 (2.3)
2 (1.2)
0 (0)
2 (1.2)
2 (1.2)
1 (0.6)
8 (1.6)
7 (1.4)
1 (0.2)
2 (1.1)
5 (2.9)
5 (2.9)
12 (2.3)
0 (0)
2 (1.1)
0 (0)
1 (0.6)
1 (0.6)
2 (1.2)
1 (0.2)
5 (1.0)
Myocardial infarction
Stroke
Arterial revascularization* CABG/carotid
endartectomy/renal procedure
Peripheral vascular procedure/lower
extremity bypass
Amputation
Death†
*At the second meeting, executive committee members decided that arterial revascularization should be separated into categories: peripheral vascular disease
procedures, which included lower extremity bypasses, and other procedures, which included coronary artery bypass grafts (CABGs), carotid endarterectomies,
and renal procedures.
†All 7 patients who died are represented in this tabulation. The executive committee classified 2 deaths as stroke and myocardial infarction.
Study Therapy
100 mg of Cilostazol
50 mg of Cilostazol
Placebo
Probability of Survival, %
100
Table 7. Most Commonly Reported Potentially Drug-Related
Treatment-Emergent Adverse Events by 10% or Greater
Incidence in Any Treatment Group
All Randomized Patients
90
Adverse Event
80
0
4
8
12
16
20
24
28
Weeks Following Study Therapy
Figure 4. Probability of survival without cardiovascular morbidity and
all-cause mortality events by treatment group.
Headache*
Abnormal stool
samples*
Diarrhea*
Dizziness
Palpitations*
Cilostazol,
100 mg,
Twice
Daily
(n = 175),
No. (%)
Cilostazol,
50 mg,
Twice
Daily
(n = 171),
No. (%)
Placebo
(n = 170),
No. (%)
Total
(n = 516),
No. (%)
60 (34.3)
26 (14.9)
40 (23.4)
25 (14.6)
25 (14.7)
6 (3.5)
125 (24.2)
57 (11.0)
21 (12.0)
18 (10.3)
20 (11.4)
17 (9.9)
15 (8.8)
8 (4.7)
7 (4.1)
8 (4.7)
0 (0)
45 (8.7)
41 (7.9)
28 (5.4)
*P,.05.
moderate intermittent claudication should first be managed more conservatively by modifying risk factors such
as smoking, sedentary lifestyle, and diet, which can improve overall cardiovascular risk.10 However, patients who
stop smoking and increase their walking exercise may
see only a modest improvement in walking ability, and
they must then adapt their lifestyle to a residual disability. Such patients might benefit from a medication that
could produce even a limited improvement in walking
ability.
Cilostazol has a number of physiological effects that
may contribute to symptom relief in patients with intermittent claudication. Cilostazol inhibits platelet aggregation in a dose-dependent manner in the presence or
absence of endothelial cells, although their presence potentiates this inhibitory effect.11,12 In a small, doubleblind, crossover study,13 cilostazol inhibited thromboxanestimulated platelet aggregation more effectively than
aspirin or ticlopidine hydrochloride. The inhibition of
primary and secondary platelet aggregation by cilostazol may have relevance to claudication through reduction in inflammatory cytokines stimulated by the ischemia reperfusion cycle of exercising muscle with a
restricted blood supply.14 Patients with intermittent clau-
dication also have impaired fibrinolysis associated with
elevated plasminogen activator inhibitor.15 Experimentally, the phosphodiesterase inhibitor HL 725 has been
observed to decrease plasminogen activator inhibitor messenger RNA levels.16 However, this clinical trial did not
attempt to assess whether such effects occurred. Cilostazol produces mild vasodilation by direct action on vascular smooth muscle by increasing intracellular cyclic
adenosine monophosphate. This effect blocks the release of calcium ions from intracellular storage granules, inhibiting contractile protein function.17 Nonspecific vasodilatory effects such as palpitation or slight heart
rate increase were observed in this study, but the significance of this in terms of claudication symptom relief is
unknown. Cilostazol also inhibits replication and growth
of rat vascular smooth muscle cells in tissue culture.18
Cilostazol was approved by the Ministry of Health
and Welfare in Japan in 1988 for the treatment of intermittent claudication, and approximately 725 000 patients have been treated with cilostazol in Japan since
1988. Pentoxifylline, which was approved by the Food
and Drug Administration in 1984, was introduced in Eu-
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Investigators
J. Michael Bacharach, MD, and Robert A. Graor, MD,
Cleveland Clinic Foundation, Cleveland, Ohio; Hugh G.
Beebe, MD, Jobst Vascular Center, Toledo, Ohio; Dennis
G. Caralis, MD, Rush-Presbyterian Hospital, Chicago, Ill;
John Castronuovo, MD, Morristown Memorial Hospital,
Morristown, NJ; Anthony Comerota, MD, Temple University Hospital, Philadelphia, Pa; Philip Comp, MD,
University of Oklahoma Health Sciences Center, Oklahoma City; John Corson, MD, University of Iowa Department of Surgery, Iowa City; Jack Cronenwett, MD, Dartmouth Hitchcock Medical Center, Lebanon, NH; Robin
Crouse, MD, Bowman Gray School of Medicine, WinstonSalem, NC; Bruce Cutler, MD, University of Massachusetts Medical Center, Worcester; Ron Dalman, MD, V.A.
Medical Center Department of Vascular Surgery, Palo Alto,
Calif; Michael Dalsing, MD, Wishard Hospital, Indiana University, Indianapolis; David L. Dawson, MD, Wilford Hall
Medical Center, Lackland Air Force Base, San Antonio, Tex;
Robert Fried, MD, Paoli Memorial Hospital, Paoli, Pa;
Roger Gregory, MD, Norfolk Surgical Group, Norfolk, Va;
Sushil Gupta, MD, MetroWest Medical Center, Framingham, Mass; J. Alan Herd, MD, The Methodist Hospital,
Houston, Tex; Glenn Hunter, MD, University of Arizona
Health Sciences Center, Tucson; Michael Jaff, DO, and
Gerald Dorros, MD, Dorros-Feurer Foundation, Milwaukee, Wis; Richard Kempczinski, MD, University of Cinncinnati Medical Center, Cincinnati, Ohio; Tom Kerr, MD,
Bay Pines Medical Center, Bay Pines, Fla; John B. Kostis,
MD, UMDNJ-Robert Wood Johnson Medical School, New
Brunswick, NJ; Parry B. Larsen, MD, Miami Heart Institute, Miami Beach, Fla; Michael Lilly, MD, University of
Maryland at Baltimore; Walt McCarthy, MD, Northwestern University Medical School, Chicago, Ill; James O. Menzoian, MD, Boston University Medical Center, Boston, Mass;
T.A. Don Michael, MD, and Brijesh Bhambi, MD, Central Cardiology Medical Clinic, Bakersfield, Calif; Barry L.
Molk, MD, Aurora Denver Cardiology Association, Aurora, Colo; Samuel Money, MD, Ochsner Medical Foundation, New Orleans, La; Steve Panian, MD, St. Joseph Hospital Research Department, Denver, Colo; Jacob Robison,
MD, Medical University of South Carolina, Charleston;
David Sheps, MD, University of North Carolina, Chapel
Hill; Anton Sidawy, MD, Chief of Vascular Surgery, Surgical Service 112 VA Medical Center, Washington DC; Geza
Simon, MD, Hypertension Clinic VA Medical Center, Minneapolis, Minn; James Smith, DO, Galichia Medical Group,
Wichita, Kan; Eugene Strandness, MD, University of Washington Hospital, Seattle; and Albert Yellin, MD, LAC and
USC School of Medicine, Los Angeles, Calif.
rope more than 20 years ago and remains an agent widely
used for the treatment of intermittent claudication in the
United States. Its mechanism of action differs distinctly
from that of cilostazol. Pentoxifylline is a xanthine derivative possessing rheologic properties that improve red
blood cell flexibility, reducing blood viscosity and increasing muscular blood flow.19 Clinical studies20,21 have
shown that pentoxifylline improves both pain-free and
maximal walking distances in patients with intermittent claudication. In a large double-blind study, pentoxifylline improved pain-free walking distance by 59% after 24 weeks of treatment (P = .11) compared with placebo.
The mean change in maximal walking distance in the pentoxifylline group was 38% (P = .19) compared with placebo.20 However, the clinical benefit of pentoxifylline has
been questioned.22 Newer vasodilators such as nafronyl
oxalate23 and buflomedil24 have also demonstrated improvement in pain-free walking distance. Platelet aggregation inhibitors such as ticlopidine25,26 and metabolic
agents such as L-carnitine27 have also shown some promise in improving walking ability in patients with intermittent claudication.
Patients in this trial were assessed by constant-load
treadmill testing at a 12.5% grade and a speed of 3.2 km/h.
Criticisms of this method, as opposed to graded treadmill testing, include observations supporting the “learning curve” placebo effect,28 the problem of using a single
stress level for a population with a heterogeneous walking ability, and the likelihood that constant-load testing
may underestimate the therapeutic effects of a study medication.29 Despite this possibility, we showed a clear benefit with cilostazol. We chose to use constant-load treadmill testing because it is well accepted by patients and,
more importantly, it provides a consistent comparison
with the existing literature for more than 2 decades.
The results of this study showed that cilostazol produces a dose-dependent improvement in treadmill walking distance in patients with intermittent claudication,
which progressively increased during the 24 weeks of
treatment. At week 24, patients who received cilostazol,
100 mg, twice a day increased their ability to walk without stopping by 129.1 m compared with baseline. Patients who received cilostazol, 50 mg, walked 67.3 m more
without stopping compared with baseline. These results are clinically and statistically superior to the 26.8
m increase in maximal walking distance seen in the placebo group. Minor adverse effects were fairly common
but usually self-limited and caused only a few patients
to ask to discontinue use of the medication.
Cilostazol, 100 mg or 50 mg, twice a day was consistently more effective than placebo in improving
walking distances, suggesting that this medication may
be a useful new tool in the management of intermittent
claudication.
Accepted for publication January 25, 1999.
This study was sponsored in part by Otsuka America
Pharmaceutical Inc, Rockville, Md.
We gratefully acknowledge Jacqueline Stedman, MPH,
Jobst Vascular Center, for preparation and revision of this
manuscript.
Reprints: Hugh G. Beebe, MD, Jobst Vascular Center,
2109 Hughes Dr, Toledo, OH 43606 (e-mail: hbeebe
@jvc.org).
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